VUR is a condition that mostly occurs in young children and involves backflow of urine from the bladder through the ureters into the kidneys and may lead to life-threatening damage to the kidneys. VUR may involve a single or double urinary collecting system i.e. a single ureter (unilateral) or both ureters (bilateral). The need for a non-invasive method of detecting Vesicoureteral Reflux (VUR) in children is clear based on the levels of anxiety observed in patients, parents and practitioners during a Voiding Cystourethrogram (VCUG) procedure, which is the current gold standard for diagnosing VUR. In this context detection includes the initial diagnosis of the condition as well as monitoring a patient that has already been diagnosed to determine if the condition has resolved or progressed as well as monitoring a patient following surgery to determine if the condition has resolved or progressed.
Primary VUR mostly occurs in young children (<5 years). It is estimated to be prevalent in 1-2% of the paediatric population and in 30% to 40% of children presenting with a Urinary Tract Infections (UTIs). VUR is a risk factor for renal parenchymal damage (RPD) or renal scarring. In the case of extensive scarring, renal injury may result in hypertension, decreased renal function, proteinuria and in certain cases End Stage Renal Disease (ESRD). In a prospective, population-based registry of children in Italy with Chronic Renal Failure (CRF), VUR was the leading single cause of CRF accounting for 25.4% of all patients with CRF.
Cohorts of patients who will benefit from the present invention includes patients presenting with UTIs (in particular those under 5 years), children with hydronephrosis and siblings and children of those with VUR.
Currently, when a child is referred to a radiologist with suspected VUR, they may be evaluated using Renal Bladder Ultrasound (RBUS), Voiding Cystourethrogram (VCUG), Nuclear Cystogram and or Dimercaptosuccinic Acid (DMSA). Each of these methods, currently used to assess patients with suspected VUR have at least one major drawback associated with it:                VCUG is the gold standard for grading VUR, however it involves both catheterisation and significant radiation exposure. During a VCUG a catheter is placed in the patient's urethra and a radiopaque contrast is instilled through the catheter into the bladder. The kidney(s), ureter(s) and bladder are observed as the bladder is filled and fluoroscopy is used to image the patient during urination to detect VUR.        RBUS it is not considered to be a reliable indicator of VUR (approximately 26% accurate).        DMSA is an expensive test, involves significant radiation exposure and must be carried out by nuclear medicine specialist. DMSA may not detect VUR, but is used to indicate if there is already damage in the kidneys.        Nuclear Cystograms also require catheter passage and radiation exposure to accurately detect VUR. Radionuclide is instilled into the bladder and the patient is imaged using a gamma camera. Radiation exposure is reduced, however image quality may be poor.        
If VUR is diagnosed or treated, repeat tests are required at regular intervals to determine if reflux has resolved or progressed. Repeat VCUG tests are often avoided based on levels of anxiety experienced by child, parent and treating physician during initial VCUG evaluations. Changes in volume of urine in the kidney at defined time points, namely as bladder pressure increases during micturition or filling, or as bladder pressure increases as pressure is applied to the abdomen and hence to the bladder, either manually or by the system itself, are indications for Vesicoureteral Reflux (VUR). If a patient suffers from VUR the impedance within the kidney(s) and or ureter(s) will increase during urination, if no VUR is present there may be little or no change observed in the kidney(s) and or ureter(s).
Bioelectrical impedance measurement involves using a pair of skin contacting electrodes to feed an electrical current into the body and measuring the resulting voltages between the same or a second electrode pair at the surface of the body adjacent to the kidney(s) or ureter(s). An apparatus for measuring bioelectrical impedance is known from the U.S. Pat. No. 6,339,722B1. This bioelectrical impedance measurement system is used to determine biological parameters concerning a bodily fluid.
Electrical Impedance Tomography (EIT) provides an impedance distribution image based on changes in impedance across a plane, where the impedance distribution image is defined by the position of the electrodes. The principle for using an EIT system to display impedance distribution images relating to parts of the human body is described in US patent 20030216664A1.
The prior art describes the concept of analysing retroperitoneal bleeding, bladder conditions, bladder function and bladder volumes and gastro-oesophageal reflux using Bioelectrical Impedance. However, no document describes use of bioelectrical impedance as a non-invasive means of measuring kidney function or reflux of urine into the kidney.
Studies have assessed impedance changes in the bladder, to provide signals to patients to indicate changes in bladder volume for patients suffering from paraplegia, or patients with other conditions that show an impaired perception of bladder filling level, that may result in incontinence or damage to the urogenital system. Studies have shown a dynamic change in impedance during bladder filling and following bladder voiding using bioelectrical impedance. For example prior art that describes a device for monitoring bladder urine volume based on bioelectrical impedance includes that described in U.S. Pat. No. 5,103,835 and CN104605850 which describes a method for monitoring bladder urine volume based on EIT. EIT has also been used for monitoring haemorrhaging from the kidneys (retroperitoneal bleeding). Studies evaluate if impedance changes in the space around the kidneys can be used to provide information to healthcare workers that internal bleeding is present. This is a useful indication for monitoring patients diagnosed with a blunt kidney trauma or following surgery on the kidneys.
The prior art also describes the concept of using bioelectrical impedance and more specifically EIT to monitor gastro-oesophageal reflux (GOR). GOR occurs when gastric contents flow from the stomach towards the oesophagus. EIT has been suggested as a possible means for removing the need for patient intubation to detect GOR. However in studies which investigate the feasibility of using EIT as an alternative method for identifying GOR, it has been concluded that it is not yet possible to detect GOR using EIT accurately. The study suggests that this may be based on the deep position of the oesophagus in the body, changes observed in the oesophagus during episodes of no reflux and the impedance range of the refluxed fluid and oesophagus contents.
Based on the impedance range of the different fluids of interest, the duration and timing of the events, impact of external organs, pathophysiology of conditions, patient cohorts and organ dimensions, it would not be obvious to the skilled person that use of EIT would be suitable or effective for detection of VUR.
The Conductivity of Different Fluids:
Different biological tissues and fluids have different conductivities, where the greater the difference in conductivity between the region of interest and surrounding regions, the easier it is to detect impedance changes. For example when detecting VUR the conductivity of urine and the kidney (at a frequency of 100 kHz) are approximately 2.3 S/m and 0.17 S/m respectively, a difference of 2.13 S/m. Where, the difference between Bladder and Urine is 2.09 S/m and Kidney and Blood is 0.53 S/m. No estimate of conductivity change values during GOR could be estimated this is due to conductivity the conductivity of gastric content varies considerably, depending on what food is consumed. As a result, the impedance difference between urine and the kidney is easier to detect and in addition it may be possible to further increase the conductivity difference by using an oral solution that further increases the impedance of urine (e.g. solution with high salt or ion concentration).
Duration and Timing:
EIT systems are most suitable for detecting dynamic changes—that occur suddenly at a known period of time. Bladder filling, kidney haemorrhage and GOR are often random, and occur over prolonged, unpredictable period of time. This limits EIT's utility for these applications. In contrast, VUR occurs when surges of highly conductive fluid (urine) travel from the bladder to the ureter(s) or kidney(s) when the bladder pressure increases (e.g. urination—an event that is predictable and rapid). The simultaneous occurrence of VUR and a high pressure event provides a known period of time when a child urinates and this data may be used to feedback into the system to define the period of time of interest and the reference timeframe to gather bioelectrical impedance measurements at a base line (when no urination occurs) and during urination to detect VUR. Impact of external organs—Bioelectrical impedance measurements are influenced by external factors, including the activity of organs surrounding the region of interest. Based on this, measurements will be impacted depending on the location of the body being monitored and different data analysis methods must be used to account for activity of surrounding organs. For example, activity of organs that are in close proximity to the oesophagus need to be considered when monitoring for gastroesophageal reflux (GOR). These may include breathing (air in the lungs), the heart beating and digestion of stomach contents. In contrast the physiological parameters that may impact Vesicoureteral Reflux may include intestinal movement, breathing and volume of urine in the bladder.
The Pathophysiology of the Conditions and Patient Cohort:
Primary VUR is generally caused by a shorter than normal intramural tunnel between the bladder and the ureter and is found in children between six months and five years of age and will often resolve as the child grows. VUR is often diagnosed when the patient presents with recurrent or febrile urinary tract infections. Gastroesophageal reflux can be found in both adults and children and is often due to obesity, diet, and smoking or in certain cases a hernia. Gastroesophageal reflux is often encountered in conjunction with other gastric symptoms. Aside from urinary tract infections that are a risk factor for primary VUR. VUR is asymptomatic: the patient cannot feel when the condition occurs, whereas patients suffering from gastroesophageal reflux have distinct symptoms such as heartburn.
The Organ that Reflux Originates in and the Location where it is Measured are Different:
VUR occurs when urine travels from the bladder through the ureter towards the kidneys, however GOR occurs when gastric contents flows from the stomach towards the oesophagus. The kidney is a separate organ to the bladder, however the oesophagus is directly attached to the stomach. Gastroesophageal reflux is monitored in the oesophagus, and VUR is monitored in the kidneys after it has travelled through the ureters and thus has travelled through other space into a different organ before it is monitored. EIT results will also depend on the distance of the electrodes from the area of interest. The oesophagus is located closest to the front of the chest and the kidneys are located close to the back, just under the ribs. The electrode material and size must be selected and placed in a position to optimise the readings for each condition depending on the location of the organ.
Other groups have looked at non-invasive means for detecting VUR. WO2000027286 discloses a passive acoustic method of detecting the presence or absence of VUR in a patient, which comprises amplifying sounds from the abdomen of the patient from a time just prior to the onset of urination, and then detecting the presence or absence of an audio signal characteristic of VUR in the amplified sound. A clinical study using this method failed to interpret a signal in 11% of cases. US20100222699 discloses a non-invasive thermotherapy which heats bodily tissues and fluid (the urine in the bladder) using emitted energy and non-invasively measures the resulting temperature changes in the target and surrounding fluid and tissue (the kidneys) to detect and/or treat various physical conditions such as Vesicoureteral reflux. Safety concerns may be attributed to using microwave energy to heat internal organs in children.